# Hypoxia-Driven Functional Conversion of CAPE: From Anti-Inflammatory to Pro-Tumorigenic Action in the Human Astrocytoma Cell Line CCF-SSTG1

## TL;DR

This study shows that the natural compound CAPE can switch from reducing to promoting inflammation in brain tumor cells depending on oxygen levels.

## Contribution

The study reveals that hypoxia converts CAPE's anti-inflammatory effects into pro-tumorigenic actions in glioma cells.

## Key findings

- Under normoxia, CAPE suppressed pro-inflammatory mediator secretion.
- Under hypoxia, CAPE increased release of pro-tumorigenic factors like IL-8 and MMP-2.
- Hypoxia appears to reprogram CAPE's immunomodulatory effects in glioma cells.

## Abstract

The glioblastoma multiforme (GBM) microenvironment, characterized by hypoxia and inflammation, is a principal driver of therapeutic resistance. Although natural compounds such as Caffeic Acid Phenethyl Ester (CAPE) are investigated for their anti-neoplastic properties, their bioactivity within the distinct metabolic landscape of the tumor core remains to be fully elucidated. Taking advantage of the recognized immunomodulatory properties of CAPE and its ability to cross the blood–brain barrier, we hypothesized that hypoxia is a key factor determining its effect on glioma-associated inflammation. To test this hypothesis, we investigated the immunomodulatory effects of CAPE on the human astrocytoma cell line CCF-STTG1. Cells were cultured under normoxic and hypoxic conditions, stimulated with lipopolysaccharide (LPS) and interferon-alpha (IFN-α) to induce an inflammatory phenotype, and subsequently treated with CAPE. The secretion profiles of key cytokines (IL-8, IL-10, IL-26) and matrix metalloproteinases (MMPs) as well as pentraxin-3 (PTX-3) were then quantified using a multiplex immunoassay. Our results revealed a striking functional dichotomy. Under normoxic conditions, CAPE suppressed the secretion of key pro-inflammatory mediators. Conversely, under hypoxic conditions, CAPE significantly amplified the release of pro-tumorigenic factors, including the mediator facilitating tumor cell migration, invasion, and angiogenesis such as IL-8 and the invasion-associated metalloproteinase MMP-2. These findings suggesting that hypoxia may fundamentally reprograms the immunomodulatory potential of CAPE. However, due to limitations of study requires further validation in a broader panel of glioblastoma models.